The present invention relates to enantio- and regioselective synthesis of esters of alcohols, sugars, organometallics and glycosides and to their preparation using enzyme mediated transesterification. More particularly, the present invention relates to enzyme catalyzed irreversible transesterification using enol esters as transacylation reagents.
Hydrolytic enzymes such as lipases, esterases, and proteases have been used extensively as catalysts in enantioselective syntheses. Whitesides, G. M., Wong, C-H. Angew. Chem. Int. Ed. Engl. 24 (1985) 617; Jones, J. B. Tetrahedron 42 (1986) 3351; Roberts, S. M. Chem. Br. (1987) 127; Akiyama, A., Bednarski, M., Kim, M. J., Simon, E. S., Waldmann, H. I., Whitesides, G. M. Ibid. (1987) 645. Because of their relatively high stability in organic media, many hydrolytic enzymes also can be used in organic solvents for certain types of transformation which are difficult to do in water. The most common reactions are esterase and lipase-catalyzed stereoselective esterifications and transesterifications. Klibanov, A. M. CHEMTECH (1986) 354-9; Klibanov, A. M., Cambou, B. J. Am. Chem. Soc. 106 (1984) 2687-92. Chen, C-S., Wu, S-H., Girdaukas, G., Sih, C. J. J. Am. Chem. Soc. 109 (1987) 2812-17; Guo, Z. W., Sih, C. J. Ibid. 110 (1988 ) 1999-2001; Gil, G., Ferre, E., Meou, A., Petit, J. L., Triantaphylides, C. Tetrahedron Lett.28 (1987) 1647; Yokozeki, K., Yamanaka, S., Takinami, K., Hirose, Y., Tanaka, A., Sonomoto, K., Fukui, S. Eur. J. Appl. Microbiol. Biotechnicol 14 (1982) 1; Tambo, G. M. R., Schar, H-P., Busquets, X. F., Ghisalba, O. Tetrahedron Lett. 27 (1986) 5705-10; Belan, A., Bolte, J., Fauve, A., Gourey, J. G., Veschambre, H. J. Org. Chem. 52, 256-60. Langrand, G., Baratti, J., Buono, G., Triantaphylides, C. Tetrahedron Lett. 27 (1986) 29-32.
One disadvantage of enzyme catalyzed hydrolytic reactions is that they are very slow compared to simple hydrolyses. Langrand, G., Baratti, J., Buono, G., Triantaphylides, C. Tetrahedron Lett. 27 (1986) 29-32. In addition, the products produced by enzymatic hydrolyses very often have to be separated from other by-products (particularly alcohol generated from the acylating reagent). Due to the reversible nature of these reactions, and due to the same stereoselectivity of the enzyme catalysis in both directions, the optical purity of the product obtained decreases as the reverse reaction proceeds. This situation is illustrated in FIG. 1 where a racemic alcohol is to be resolved via an enzymatic esterification (R"=H) or transesterification. ##STR1##
As shown in FIG. 1, if the D-isomer is a better substrate than the L-isomer for the enzyme, accumulation of the D-ester and the unreactive L-alcohol will be observed. In the reverse reaction, however, the D-ester is a better substrate and will be converted to the D-alcohol. The enantiomeric excess of both the D-ester and the L-alcohol therefore will decrease progressively as the extent of the reverse reaction increases. This reverse reaction problem clearly has been illustrated in the kinetic resolution of menthol, Chen, C-S., Wu, S-H., Girdaukas, G., Sih, C. J. J. Am. Chem. Soc. 109 (1987) 2812-17; Guo, Z. W., Sih, C. J. Ibid. 110 (1988) 1999-2001, and can be seen in the enantioselective esterification or transesterification of meso compounds.